536
INTERACTION OF CIMETIDINE WITH 241 ±28 mg when tetracycline was given alone compared to
TETRACYCLINE ABSORPTION
SIR,-Gastric acidity may influence absorption of drugs, es-
pecially those whose dissolutionis pH dependent.’·2 The
report3 that -cimetidine increases blood salicylate concentra-
tions when coadministered with aspirin suggests that by in-
hibiting gastric acid secretion, cimetidine increases the dissolu-
tion rate and, thus, the absorption of aspirin. We have
investigated the effect of cimetidine on the bioavailability of
tetracycline, a basic antibiotic requiring low pH for optimum
dissolution and absorption.
Three men and two women (age 18-26 years, weight 47-60 kg)
took part. After an overnight fast, tetracycline hydrochloride (’Achro-
mycin’) was administered as 2x250 mg capsules with 200 ml water.
On a different occasion, each subject was also given cimetidine (’Taga-
met’), 200 mg three times daily and 400 mg at bedtime, for three con-
secutive days beginning the day before tetracycline administration.
The treatments were allocated according to a randomised crossover de-
sign, treatments being separated by a washout period of at least 7
days. As a control, the above procedures were repeated except that the
contents of the tetracycline hydrochloride capsules were dissolved in
200 ml water just before administration. Food was not permitted for
four hours after tetracycline administration when normal diet could be
resumed. Dairy products, vitamins, antacids, and any other medi-
cation were not permitted during the study. The volunteers also
refrained from alcohol and tobacco. Urine was collected immediately
before tetracycline administration’ (blank), then hourly up to twelve
hours and then as necessary up to seventy-two hours. Each volunteer
noted his urine collection times and volumes. A portion of each urine
sample was frozen and assayed for tetracycline by high performance
liquid chromatography. The amount of tetracycline excreted in the
urine was calculated for each subject in each of the four treatments.
The results are presented in the figure. The coadminist-
ration of cimetidine with tetracycline decreased absorption of
tetracycline from capsules. The mean (±SEM) cumulative
amount of tetracycline excreted up to seventy-two hours was
1.Mayersohn M. Physiological factors that modify systemic drug availability
and pharmacologic response in clinical practice. In: Blanchard J, Saw-
chuk RJ, Brodie BB, eds. Principles and perspectives in drug bioavailabi-
lity. Basel: Karger, 1979; 211-73.
2. Barr WH, Adir J, Garrettson L. Decrease of tetracycline absorption in man
by sodium bicarbonate. Clin Pharmacol Ther 1971; 12: 779-84.
3. Khoury W, Geraci K, Askari A, Johnson M. The effect of cimetidine on
aspirin absorption. Gastroenterology 1979; 76: 1169.
Mean cumulative urinary excretion of tetracycline after admin-
istration to five subjects as capsules and as solution, with and
without coadministration of cimetidine.
0= tetracycline HCI (500 mg) capsules.
<t= tetracycline HCI (500 mg) capsules + cimetidine (800 mg/day).
0= tetracycline HCI (500 mg) solution.
8= tetracycline HCI (500 mg) solution + cimetidine (800 mg/day).
172 &plusmn;13 mg when administered with cimetidine, a decrease of
approximately 30% (p<0.05, paired t-test). In contrast, when
tetracycline was given in solution, the mean cumulative
amount excreted was 264&plusmn;21 mg compared to 236&plusmn;11 mg
when given in conjunction with cimetidine. This difference was
not significant.
Dissolution of tetracycline in the stomach is a prerequisite
for absorption in the small intestine because the mildly alka-
line conditions of the small intestine tend to inhibit further dis-
solution of tetracycline once undissolved drug particles reach
this point in the gastrointestinal tract. Our results indicate
that therapeutic doses of cimetidine substantially reduce the
absorption of tetracycline when the antibiotic is administered
orally, as capsules. The insignificant effect of cimetidine on the
absorption of tetracycline from solution indicates that cimeti-
dine per se, does not affect the absorption of the antibiotic, but
that by lowering gastric acidity, it establishes an unfavourable
environment for gastric dissolution and, subsequently, absorp-
tion in the small intestine.
Bioavailability is a well recognised problem with oral tetra-
cycline preparations, and the reduced absorption in the pre-
sence of cimetidine is of special concern since it could lead to
therapeutic failure. Now that cimetidine is frequently prescrib-
ed, often for long periods, its interaction with drugs whose
_ absorption is related to gastric acidity should be investigated
further. -
Department of Clinical Pharmacology,
J. J. COLE
Princess Alexandra Hospital, B. G. CHARLES
Brisbane, Queensland 4102, Australia P. J. RAVENSCROFT
ARTHROPATHIES AND SCHIZOPHRENIA
SIR,-We have previously reported an association between
HLA-B27 and chronic paranoid schizophrenia.’ Using similar
diagnostic and laboratory methods, - Mendlewicz and Lin-
kowski2 also found an increased frequency of HLA-B27 in
schizophrenic patients, although the difference was not signifi-
cant when compared with a control group.
Bearing in mind (a) that HLA-B27 is highly correlated with
some forms of arthropathies3 and (b) that arthropathies and
schizophrenia rarely occur together,4-7 we wondered if HLA-
B27 could serve as a genetic marker for both arthropathy and
schizophrenia. To investigate this point we carried out the fol-
lowing studies:
(1) 16 patients with chronic schizophrenia bearing
HLA-B27 were investigated with clinical, radiological, and
laboratory tests for any form of arthropathy.
(2) HLA antigens were typed in 288 patients with clinical,
radiological, and laboratory features of an arthropathy (anky-
losing spondylitis, Reiter’s syndrome, juvenile rheumatoid
arthritis, &c). 131 carried HLA-B27 and 157did not. By
means of the cumulative psychiatric case register at this insti-
tute we compared the incidence of psychiatric diagnoses
between these two subgroups (with and without HLA-B27).
The methods are described in detail elsewhere.8
1. Gattaz WF, Beckmann H. HLA-antigens and schizophrenia. Lancet 1980,
i: 98-99.
2. Mendlewicz J, Linkowski P. HLA-antigens and schizophrenia. Lancet 1980;
i: 765.
3. Svejgaard A, Platz P, Ryder LP, Staub-Nielsen L, Thomsen M. HLA and
disease association: a survey. Transplant Rev 1975; 22: 3-43.
4. Nissen HA, Spencer KA. The psychogenic problem (endocrinal and metabo-
lic) in chronic arthritis. N Engl J Med 1936; 214: 576-81.
5. Mellsop GW, Whittingham S, Ungar B. Schizophrenia and autoimmune ser-
ological reactions. Arch Gen Psychiat 1973; 28: 194-96.
6. Mellsop GW, Koadlow L, Syme J, Whittingham S. Absence of rheumatoid
arthritis in schizophrenia. Aust NZ J Med 1974; 4: 274-352.
7. &Ouml;sterberg E. Schizophrenia and rheumatic disease. Acta Psychiat Scand
1978; 58: 339-59.
8. Gattaz WF, Ewald RW, Beckmann H. The HLA system and schizophrenia.
a study in a German population. Arch Psychiat Nervenkr 1980; 228:
205-11.